PROJECT ABSTRACT/SUMMARY A major obstacle to long-term control and cure of HIV has been the persistence of HIV in reservoirs that contain latently infected, resting, and productively infected CD4+ T cells. The single example of cure of HIV has provided evidence that the search for a cure is an achievable goal. Furthermore, the mechanism of cure in this case (transplantation with CCR5-negative cells) emphasizes that cell and gene therapies represent perhaps the most promising approach to cure. Here we propose a multi-investigator program to evaluate the leading cell and gene therapy approaches to HIV cure, and to study the biology of the HIV reservoir in patients and nonhuman primates undergoing these therapies. We have assembled a team consisting of leaders in the fields of HIV, cell and gene therapies, NHP models, and clinical research. We propose 3 highly integrated Initial Research Foci in pursuit of our overall goal, and 5 Scientific Research Supports that will facilitate these projects. Initial Research Focus 1 (IRF1), HIV-Resistant Anti-HIV CAR T Cells, will be led by Dr. Lawrence Corey, Member in the Vaccine and Infectious Disease Division at Fred Hutch, and co-founder and Senior Science Advisor of our private sector partner, Juno Therapeutics; Dr. David Rawlings, Director of the Center for Immunity and Immunotherapies at Seattle Children's Research Institute; and Dr. Thor Wagner, Associate Professor at Seattle Children's Research Institute. IRF2, eCD4-Ig based therapy for HIV cure, will be led by Dr. Michael Farzan, Professor and Vice Chair, Department of Immunology and Microbial Science, The Scripps Research Institute Florida. IRF3, Genetic protection of T cells after therapeutic vaccination, will be directed by Dr. James Mullins, Professor of Microbiology, and Dr. Deborah Fuller, Associate Professor of Microbiology, at the University of Washington. We hypothesize that these cell and gene therapies offer the ideal and perhaps most promising tools with which to meet the dual goals of 1) eliminating latently-infected cells after viral reactivation, and 2) improving the host's ability to control unpredictable reactivation events from a therapeutically-reduced reservoir.